The objective of studying the metabolism of naloxone and naltrexone is presently focused upon the modifications produced by morphine. The enzymatic aspect of stereospecific reduction of naloxone to 6 alpha- and 6 beta-naloxol is being studied with the aim toward understanding how morphine administration stimulates the increase in formation of 6 alpha-naloxol from naloxone in the guinea pig. Further work involves characterizing the role of the cofactors NADPH and NADH, possible allosteric effects of morphine, temperature dependence, etc. for this system. This system will be compared also to other reducing enzyme cytosol systems such as for menadione, camphor, steroids, etc. This enzymatic system affords a means of studying drug receptor interaction in a functioning receptor, the enzyme. Also, studies will be continued on the single dose effect of morphine to enhance the brain concentration of subsequently administered naloxone. Studies will be aimed toward assessing the specificity of this effect since our preliminary experiments indicate that morphine pretreatment will increase the brain concentration of etorphine, a narcotic agonist.